Composition and method for rapidly inducing an endogenous ketosis

ABSTRACT

A composition and method for rapidly inducing a state of endogenous ketosis, the composition including: about 26.66-28.57 percent by mass of alpha lipoic acid; about 0.01-0.02 percent by mass of chromium picolinate; about 47.61-49.99 percent by mass of L-arginine; and, about 23.33-23.81 percent by mass of calcium carbonate. The method includes restricting carbohydrate consumption to a maximum dosage of about 20 grams prior to consumption of the composition and wherein consumption of the composition is on an empty stomach. About thirty minutes after consumption of the composition the user performs moderate intensity exercise. About three hours after consuming a first dose the user tests for a presence of ketones in urine utilizing at least one sodium nitroprusside urine ketone reagent strip.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 62/196,314 entitled “AN ORAL DIETARY SUPPLEMENT THAT RAPIDLY INDUCESKETOSIS VIA GLUT PROTEIN EXPRESSION” filed on Jul. 24, 2015, the entiredisclosure of which is incorporated herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable.

TECHNICAL FIELD

The present invention relates generally to the field dietarysupplements, and more particularly relates to supplements for promotingweight loss, preserving lean body mass, improving insulin resistance,and improving lipid profile.

BACKGROUND

Approximately 34.9% of all Americans are obese and this percentage ofthe United States population represents more than 78.6 million Americanadults. Currently, the CDC estimates that at least 70.7% of Americanadults over the age of twenty are overweight which is defined as a BMIof 25-29.9 with a BMI of 30 and above indicating obesity. Two of theleading causes of mortality in the United States are cardiac associatedconditions and Type 2 Diabetes Mellitus, both of which have beendirectly linked to obesity through increased risk. The CDC estimatesthat the annual cost of obesity, in 2008 dollars, in the United States,exceeds more than $147 billion with obese adults requiring additionalmedical expenses of $1,429.00 over their non-obese adult counterparts.

The World Health Organization (WHO) has stated that the obese worldpopulation has doubled since 1980. The WHO lists current world obesitystatistics on their website and makes three statements concerningobesity: 1.) 42 million children were overweight or obese in 2013; 2.)More than 1.9 billion adults were overweight or obese in 2014; and, 3.)Obesity is preventable. Clearly an obesity pandemic exists, and twoimportant questions must be considered. Why has the world overweight andobese population continued to grow even though new medical technology iscontinuously produced and dietary guidelines continuously updated? Whyhave the majority of diets recommended by health professionals failed tohave an impact on the obese population or slow the growth of theoverweight population? The answers to the above questions are quitecomplex and include not only the various etiologies of obesity itselfsuch as genetics, medical comorbidities, lack of exercise, or simpleovereating: but also a widespread, misunderstanding of fundamental humanbiochemistry coupled with practice and propagation, through education,of flawed nutritional principles.

Low Calorie Diets.

At the very foundation of the low-calorie diet is the energy balanceequation in which weight change is dependent only on calories consumedvs. calories used for metabolism, essentially calories in vs. caloriesout. Low-calorie or calorie-restricted diets are arguably the mostpracticed diet methodology in the world today and are staunchly foundedin energy balance equation theory. The basic principle of any reducedcalorie diet is as follows: To lose weight, specifically from fat, anindividual must reduce caloric intake thereby creating a caloric deficitwhich the body must then make-up for by relying on its fat stores toproduce the calories needed for basal energy production. For example, itis widely taught by nutrition field professionals that 1 lb. of fatcontains 3,500 calories and by reducing caloric intake by 500 caloriesper day for 7 consecutive days an individual may lose 1 lb. of fat perweek (−500 Cal/day*7 days/week=−3,500 Cal/week=−1 lb./week). Relyingupon this method, an individual who wished effect a 10 lb. weight lossover a 10 week period must simply consume 3,500 fewer calories, perweek, for 10 consecutive weeks creating an overall deficit of 35,000calories. Further, the deficit required is 500 calories per day overalland calories may be cut from any major nutrient group—lipids,carbohydrates, or proteins. The reality is that the 3,500 calorieprincipal is nothing more than simple mathematics used to visualize theloss of a so-called pound of fat. The idea of cutting 3,500 caloriesfrom the diet to effect the loss of 1 lb. of fat could not be furtherfrom the truth when considering principals of human biochemistry andhuman adipose tissue composition.

The 3,500 calorie theory originated in the late 1950s by Max WishnofskyMD, who concluded, after reviewing previous studies on the subject, thatone pound of human adipose tissue contains approximately 3,500 caloriesof stored energy and is composed of approximately 87% lipid.

Interesting to note, is that several other researchers in the same fieldconcluded, through similar studies, that the lipid content of humanadipose tissue is highly variable and ranges anywhere from 61-94%. 1 lb.of human tissue contains 453.6 g and fat, in particular, contains 9calories per gram. Using Wishonfskys method it can be shown that 1 lb.of adipose tissue contains approximately 3,500 calories: (453.6g/lb.*0.87% lipid*9 Cal/g=3,551.7 Cal/lb.). However, applying the rangeof lipid makeup percentages to this number gives an extensive variationof how many fat calories actually make up 1 lb. of adipose tissue,2490.3-3537.5 calories. Protein may also contribute calorically toadipose tissue and was found in studies to be roughly 1-6.5% of adiposetissue make-up. Therefore, the total caloric content of 1 lb. of humanadipose tissue, accounting for lipid and protein make-up, ranges from2508.4 Cal/lb.-3655.4 Cal/lb.

Other studies have concluded that human adipose tissue makeup is highlyvariable with the water, lipid, nitrogen, and protein portions being agedependent with lipid content increasing over time as the othercomponents decrease. It is clear to see that without intimate knowledgeof one's own adipose tissue makeup, simply reducing caloric intake by3,500 calories per week could potentially result in a dietroller-coaster with unexpected results. Further, the 3,500 calorie ruleassumes body weight changes linearly over time during a dieting periodwith steady decreases in body fat percentage. This concept of linearweight change in the form of weight loss is simply not true as bothtotal body weight and fat composition may fluctuate up or down duringdieting periods while the body attempts to adapt to the diet. Concerningthe digestion of food in general, the energy balance equation simplystates that to achieve optimal energy balance calories burned throughmetabolism must equal calories consumed. The definition of one calorieis the amount of heat required to raise the temperature of one kilogramof water one degree Celsius.

The problem with calories as they relate to nutrition is that thescientific definition as given above applies to closed systems and nothuman biometabolism and this is exactly the reason that 500 calories ofbroccoli and 500 calories of sugary soda are processed differently bythe body. Throwing fuel on an already out of control fire, food industrycompanies often promote 100 calorie portion sized snacks as healthy dueto reduced calorie content however the difference between a 100 calorieapple and a 100 calorie bag of chocolate chip cookies cannot beoverlooked and to state that the two are equal is pseudoscience.Further, it is scientific fact that the digestion of protein, due to itschemical structure, requires more energy expenditure than digestion ofcarbohydrate or fat and this completely flies in the face of thewidespread belief that a calorie is a calorie regardless of its nature.

The fallacy of the low-calorie ideology is further manifest by a 2003publication from the Nutrition Department at Harvard's School of PublicHealth. The study compared the weight loss potential of various dietsbased on caloric intake by placing participants on one of three dietsfor 12 weeks: low-fat-low-calorie, low-carbohydrate-low-calorie, or lowcarbohydrate-high-calorie. The results of the study showed the groupthat lost the most weight, 23 lbs. vs. 17 lbs., was thelow-carbohydrate-high-calorie group and they lost more weight whileeating 25,000 more calories over then 12 week period than thelow-fat-low-calorie group. Further, of the two carbohydrate groups theone that ate the most calories lost the most weight, 23 lbs. vs. 20 lbs.Clearly it can be said that dietary caloric restriction or intake is notthe determining factor in either weight loss or weight gain.

The reasons that the ideology of cutting calories to lose weight haspersisted are several, and include resistance to change by thenutritional community, publication of flawed principals in textbooks andon internet webpages, and lack of a thorough understanding of how thehuman body is known to work today. A simple internet search will sufficeto show the degree to which the population at large relies upon theflawed idea of cutting 3,500 calories to lose 1 lb. of fat as numeroushealth and fitness websites advocate this method as a means to improvinghealth and an example of this is that as of this writing, the MayoClinic and The Cleveland Clinic, two highly respected medical fieldinstitutions, teach the 3,500 calorie principal to the public throughtheir respective websites as an adequate means of weight loss from fat.

Further, the 3,500 rule makes no provision for gender, exercise,compliance to diet, individual adipose tissue makeup, or intake ofvarious nutrients now known to promote fat deposition such as excessrefined carbohydrate. While following a reduced calorie diet manyindividuals lose weight initially and then subsequently hit a plateau;this plateau of decreased weight loss has been shown to be due tocaloric deficit as the body slows its metabolism with caloricrestriction. If calories are reduced too drastically for an extendedperiod of time weight loss occurs in the form of broken down muscle massdue the body metabolizing protein for energy production through aprocess called gluconeogenesis. Important to note is that not all aminoacids will yield glucose via gluconeogenesis; on average, 1.6 g of aminoacids are required to synthesize 1 g of glucose. Thus, to keep the brainsupplied with glucose at rate of at least 120 g/day, the breakdown of160 to 200 g of protein (roughly 1 kg of muscle tissue) would berequired.

Certain types of muscle tissue, due to their permanent nature, cannot bereplaced if broken down for energy production via conversion to glucoseand two of the most important types of muscle tissue, cardiac andskeletal muscle, fall into this category.

One could contend that if reducing caloric intake slows the body'smetabolism and results in loss of muscle mass via protein metabolism,what is the point of cutting calories to lose weight from fat in thefirst place? Some of the most common side effects of cutting caloriesare fatigue, hunger, headache, sluggish feeling, and cold intolerance,all signs of a metabolism that has ground to a halt. From a humanbiochemical standpoint it can be argued that cutting calories to loseweight from fat is absolutely counterproductive to the body's normalhomeostatic mechanisms.

Low-Fat Diets.

A second type of diet that is commonly practiced, but flawed in theextreme, is the low-fat diet. Advocates of this diet maintain thatexcess dietary fat directly promotes weight gain and obesity and this isdue to their belief that high fat foods such as steak, eggs, and dairyproducts like cheese, milk, and butter will cause vascular disease inthe form of plaques that occlude arteries or be deposited as excess fatin adipose tissue. This “bad fat” idea originated in the mid-20thcentury when a University of Minnesota researcher by the name of AncelKeys examined the dietary lipid intake of individuals from severalcountries and concluded that diets high in fat and cholesterol resultedin an increased deposition of atherosclerotic plaques and increasedrates of cardiovascular disease. However, Keys conclusion and subsequentpublication was shown to be flawed as he was chastised by fellowresearcher Jacob Yerushalmy, among a host of critics, for limiting hisfindings at publication to six countries instead of including data frommore than twenty countries he examined in his research. Yerushalmyshowed that Keys effectively relied upon researcher bias to draw hisconclusions due to the fact that when data was analyzed from allcountries in Keys study there was no correlation whatsoever betweenlipid consumption and cardiovascular disease. Keys presented hisfindings to the scientific community and a further study was carried outknown as the Seven Countries Study which focused on dietary fatconsumption and heart disease in individuals in seven countries fromfour geographic regions: Northern Europe, Southern Europe, The UnitedStates, and Japan. This multi-country study concluded that excessdietary lipid intake increased the risk of cardiovascular disease andobesity secondary to lipid deposition in the vasculature. This study,like Keys previous study, was flawed for multiple reasons including howthe study attempted to establish causality without even a significantcorrelation, although Keys denied this, and how it provides noexplanation for low cardiovascular disease rates in countries thatconsume high amounts of dietary lipid as seen in a typical Mediterraneandiet. Regardless of flaw, the study was the first of its kind andreceived a massive amount of media attention and helped to fostersimilar studies by health field entities as well as the U.S. governmentthat reached similar conclusions.

One similar study, the Framingham Heart Study, is an ongoing study basedon the previously postulated correlation between dietary lipid intakeand cardiovascular disease. This study is known for identifying heartdisease risk factors such as smoking, high blood pressure, lack ofexercise, and high cholesterol even though the link between highcholesterol and heart disease has been criticized as being weak. Thehighly publicized findings of the study indicate that overweightindividuals generally have higher blood cholesterol levels and are at agreater risk for heart disease. However, not highly publicized is thefinding that participants who consumed more dietary cholesterol andsaturated fat had overall lower blood cholesterol levels, exactly theopposite of what the study expected to find from the beginning. Indeed,a former director of the study, Dr. William Castelli stated: “Forexample, in Framingham, Mass., the more saturated fat one ate, the morecholesterol one ate, the more calories one ate, the lower the person'sserum cholesterol. The opposite of what one saw in the 26 metabolic wardstudies, the opposite of what the equations provided by Hegsted et aland Keys et al.”

Further, the Framingham study includes second and third generationoffspring of the original participants and it has been clearlyestablished that over 70% of individuals suffering from hyperlipidemiado so because of genetic inheritance alone. The question should be posedthat if diseases such as familial hypercholesterolemia and other geneticdyslipidemias contribute to abnormal lipid profile and cardiovasculardisease more than any other factor, including dietary lipid intake, whydo health and nutrition field experts continue to warn individuals tolimit their dietary lipid intake? Further, the genetic dysregulation oflipid homeostasis by the liver is exactly the reason individuals withhyperlipidemia derive the most benefit from lipid lowering drugs thatinhibit the HMG-CoA reductase and PCSK9, two enzymes directly involvedin cholesterol production and metabolism in the body; not by reducingdietary lipid consumption or trimming the fat off of their steak.

The end result of this type of research was a fear of dietary lipidinstead of an honest effort to understand its role in human metabolism.Thus in lieu of consuming dietary fat nutritionists and physiciansrecommended a low-fat, high carbohydrate diet with carbohydrate contentmaking up some 60% or more of the new recommendations. There immediatelyarose a huge market industry for low-fat food products, but theseproducts came with catastrophic nutritional repercussions. Low-fat foodproducts often have excess added sugar which has been shown to be thereal cause of weight gain. Indeed, a study on the consumption of sugarintake and obesity rates in 1,700 individuals in Norfolk, UK concludedthat the individuals who consumed the most sugar were 54% more likely tobe obese. Further, the individuals in the study who were found to beobese misrepresented the amount of sugar they actually consumed dailythrough underreporting of the amount consumed. The only conclusion thatcan be drawn from the study is that excess sugar consumption is directlylinked to obesity and the average individual does not know how muchsugar they are consuming daily which results in unexpected weight gainwith increased body fat percentage.

A 1999 study on low-fat diets and low-fat food products found that theywere not associated with improved cholesterol levels, quite theopposite, these diets were associated with worse overall LDL (badcholesterol) levels. In a 2015 meta-analysis of research into thelow-fat diet and low-fat dietary guidelines Harcombe et al found thatthere was absolutely no scientific basis to the 1977 and 1983 U.S.McGovern committee guidelines cautioning individuals to refrain from orlimit dietary fat intake. A similar reversal of stance has recently beenadopted by the American College of Cardiology and the American HeartAssociation on the dietary intake of cholesterol since it wasblacklisted for years by nutritionists as extremely harmful to health. A2010 meta-analysis, of twenty-one different studies involving 347,747patients, on the relationship between saturated fat intake andcardiovascular disease concluded that there is no evidence to suggestthat saturated fat contributes to cardiovascular disease. However, in astudy examining the consumption of low-fat food products and theireffect on overall health the conclusion was clear: excess sugar found inlow-fat diet food products contributed directly to obesity whichdirectly increases risk of cardiovascular diseases.

One of the major problems of applied nutrition concerning any dietregimen is the compliance of dieters. This lack of compliance can easilybe observed when dieting individuals experience negative diet associatedsymptoms such as headache, fatigue, hunger, weakness, frustration, orlack of progress and discontinue their diet. Medical field advancementshave come about in the form of gastric bypass surgeries for individualswho are obese; however, these procedures are invasive and often requirea basal loss of weight before it is safe for a patient to undergosurgery. Also, patients who undergo gastric bypass surgery often havelifelong complications such as dumping syndrome, chronic constipation,and malabsorption that are surgery induced secondary gastrointestinaltract manipulation. From a pharmacological standpoint, medications havebeen researched and formulated to aid in weight loss by speeding upmetabolism to burn more calories, but virtually all medications haveside effects which may negatively impact a patient's nervous system,immune system, endocrine system, or psychiatric state. Concerningmedical intervention, some individuals may be afraid or intimidated bysurgical procedures or drug regimens and in some instances medicalintervention is recommended when it may not even be indicated.

Having discussed two major diets as well as surgical and drugintervention that healthcare professionals often prescribe and dieterswillingly undertake it can plainly be seen that the current obesitypandemic will continue unless some serious intervention occurs. Thisintervention must occur via two pathways: 1)—Proper education ofnutrition and healthcare professionals, as well as patients, on researchproven causes and treatments of obesity. 2)—Application of nutritionalprinciples or vehicles for weight loss that have been shown to becurrent, efficacious, and science based.

Considering the previous information there currently exists anon-traditional diet regimen, known as the low-carbohydrate or ketogenicdiet, that allows an individual to lose weight from fat, spare musclemass, and avoid common symptoms of hunger, fatigue, headache, andfrustration which are associated with other diets. Important tounderstand is that there are multiple variations of low-carbohydrate,ketogenic diets and examples include the Atkins diet, South Beach diet,the Paleo diet, and cyclic ketogenic diet. Many individuals will arguethat these diets are completely different from one another, however atthe micronutrient and cellular levels all low-carbohydrate, ketogenicdiets are essentially the same as all rely upon a foundation ofrestricting excess sugars, in the form of carbohydrates, to induce fatmetabolism for weight loss. When excess dietary carbohydrate isrestricted the body must find a way to compensate for energyrequirements and does so thorough the production of energy intermediatesknown as ketones. For the purposes of this invention, any diet,regardless of specific name, that restricts carbohydrate to a minimumand results in fat metabolism with endogenous ketone production will bereferred to as a ketogenic diet.

Ketogenic Diets.

Under normal conditions, the body mainly depends on the metabolism ofglucose to supply the energy needed for cellular function, and therequired glucose is normally derived from the consumption of dietarycarbohydrates. These carbohydrates can be from multiple sources and beeither simple or complex such as table sugar or starch. Once ingested,carbohydrates are degraded into their respective sugars, mainly glucose,and distributed to cells across the body via the bloodstream. Cells withthe aid of the hormone insulin take up glucose from the blood andconvert it to an intermediate known as acetyl-CoA which is then used toproduce adenosine-triphosphate (ATP), the high energy compound used bycells for metabolic function. While all cells in the body rely onglucose for immediate energy production the majority of cell types donot have the capacity to store glucose for future use. However skeletalmuscle and liver cells can use glucose to form glycogen, a polymer ofglucose molecules linked together and sequestered for future use.Further, glycogen stored within individual muscle cells can only bedegraded and used by that cell; liver glycogen however functions as atotal body reserve of glucose. This specific ability of the liver tofunction as a total body glycogen/glucose reserve is due to the presenceof the enzyme glucose-6-phosphatase in the liver. After liver glycogenhas been degraded into individual glucose molecules,glucose-6-phosphatase catalyzes the transformation of these molecules sothat they can exit the liver and enter the blood stream; through thismechanism the liver works to maintain normal blood glucose levels andprovide a source of glucose to all tissues as needed. Muscle and liverglycogen storage capacities vary with individual, but total body muscleglycogen storage capacity is around 400 g and the liver stores around90-110 g. The liver functions to maintain a specific blood glucose levelin order to provide cells with a constant energy source and normal bloodglucose ranges from 80-100 mg/dL or about 4 g of total glucose in theblood at any given time. The brain requires around 6-7 g of glucose perhour or at least 120 g per day, and red blood cells function solely onglucose derived from the blood. As blood glucose levels fall due toutilization by tissues glycogen is degraded in the liver and glucose isreleased into circulation for cellular uptake. Constant output ofglucose by the liver can deplete its glycogen stores quickly if notreplenished through carbohydrate consumption as the liver, containingroughly 90-110 g of glycogen can only meet the body's metabolic needsfor a short period of time on its own. In the fed state when the musclesand liver have stored their capacity of glycogen and ATP levels arehigh, excess glucose is shuttled into adipocytes and stored as fat. Asthe intake of carbohydrate increases beyond the body's needs muscle andliver glycogen stores stay at maximum capacity and excess dietarycarbohydrate is converted into glucose and subsequently fat and storedat a higher rate. The excess production and storage of fat in adiposetissue results in obesity with its secondary comorbidities such asmetabolic syndrome, diabetes, heart disease, neurodegenerative diseases,and vascular diseases. In most Western diets, the major form of dietarynutrient consumed is carbohydrate in excessive amounts. The NationalAcademies Health and Medicine Division Food and Nutrition Board set therecommended daily allowance (RDA) and adequate intake (AI) formacronutrients in the United States and Canada and recommend an intakeof 130-210 g/day of carbohydrate for men and women as well as women whoare pregnant or lactating and the U.S. FDA recommends a minimum intakeof 300 g. In view of these recommendations excess carbohydrateconsumption in the United States is easily seen as the sugar content ofthe most popular size soda, the one serving, twenty ounce bottle, fromtwo of the most popular soft drink companies contains 69 g and 79 g ofsugar respectively which represents 25% or more of the total dailyrecommendation. Indeed, studies have shown that more than half of allindividuals in the United States consume sugary drinks such as soda on adaily basis and sugary drinks have been shown to make-up the top caloriesource of the average teenage diet. This overconsumption of carbohydratecorrelates directly with the current obesity numbers seen in the UnitedStates and the world at large.

In periods of fasting, extended exercise, or restricted carbohydrateintake muscle and liver glycogen stores are depleted. The result ofglycogen depletion, without restoration, is that the body must find away to compensate for energy requirements and does so through hepaticbeta-oxidation of stored fat with subsequent production of energyintermediates known as ketones and ketones can be used by every cell inthe body for energy production purposes.

Concerning ketone production, there are three molecules generally andhistorically referred to as ketones or ketone bodies which are producedfrom beta-oxidation of fatty acids within the liver—acetone,acetoacetate (AcAc), and beta-hydroxybutyrate (BHB). However, before thefunction of these molecules is put forth their origin must be discussedas there currently exists a literal myriad of confusion regarding theterms ketone and ketone body.

Acetone and acetoacetate are structurally and functionally ketonesaccording to the chemical definition of a ketone—a carbonyl carbon boundto two other hydrocarbon groups. Acetoacetate can further be classifiedas a ketoacid due to the fact that it contains a ketone group and acarboxyl group. Beta-hydroxybutyrate is chemically classified bystructure as a carboxylic acid or hydroxyacid and referring to thecompound as a ketone, ketoacid, or even ketone body is erroneous as ithas no ketone component. The terms “ketone body” or “ketone bodies” havecome to be widely used for purposes of referring to all three moleculesas a group, however this term is archaic and somewhat confusing due todifferences in both structure and function of all three molecules.

The origin of the term ketone body dates to the turn of the 20thcentury. In 1908 a researcher by the name of Magnus Levy discovered thatdiabetic or fasting patients had a fruity odor component to their breathwhich was characterized as that of the ketone acetone. Unknown toresearchers at the time was that acetoacetate is the first ketoneproduced by the liver in a ketogenic state and is a highly unstablemolecule which undergoes spontaneous decarboxylation to form the ketoneacetone or is converted to the carboxylic acid beta-hydroxybutyrate.Early 20th century researchers did not understand the complexinteraction between acetone, acetoacetate, and beta-hydroxybutyrate.However, researchers did know that diabetics suffered from severeacidosis with accompanying acetone breath and they labeled theuncharacterized substances that accumulated in the blood and urine ofdiabetic patients' acetone bodies. The term acetone bodies was laterchanged to ketone bodies because acetone is a ketone. Indeed, a 1904publication titled Clinical Urinology details the examination of severalsubstances in the urine of diabetics while referring to them as acetonebodies while attempting to characterize their nature and function.

Acetone bodies is a term that had its roots in earlier research relatedto the discovery of acetoacetate and beta-hydroxybutyrate. In 1865acetoacetate was discovered in the urine of diabetic patients and in1884 researchers, Minkowski and E. Kulz simultaneously discovered andisolated the substance β-oxybutyric acid, or beta-hydroxybutyric acid.Further investigation showed that mild oral supplementation ofbeta-hydroxybutyric acid resulted in the urinary excretion ofacetoacetate and acetone and high volume supplementation ofbeta-hydroxybutyric acid led to the excretion of all three substances.Due to the fact that administration of beta-hydroxybutyric acid resultedin the production and excretion of acetoacetate and acetone,beta-hydroxybutyrate was thought to be the parent molecule of the three.Later Magnus Levy went on to deduce that the increased level of breathacetone present in diabetic or fasting patients was secondary tobreakdown of fatty acids and occurred along with production ofacetoacetate and beta-hydroxybutyrate which were measurable in the urineand blood and the three molecules became an inseparable trio for betteror worse. Finally, in the 1950s researchers Kaplan and Lipmanndiscovered that acetoacetate was the central molecule which underwentchemical change to form acetone or beta-hydroxybutyrate, however by thistime the term ketone bodies had stuck and continues to be used today.

The problem arising from utilization of the term ketone bodies has to dowith the fact that because acetone, acetoacetate, andbeta-hydroxybutyrate have been referred to as ketone bodies for so longbeta-hydroxybutyrate has actually come to be erroneously referred to asa ketone itself. This mislabeling can be seen in the waybeta-hydroxybutyrate is referred to not only as a ketone body, but as aketone in numerous publications including scientific articles andnutrition text books, health and fitness magazines, and internetwebsites and this is due to the assumption that a substance with aketone-body must naturally contain a ketone component which should bethe case but it is not. Further, the mislabeling of beta-hydroxybutyrateas a ketone or ketone body is highly misleading for those individualsnot familiar with the chemical structure or biological function of themolecule as these individuals automatically think that an increasedblood beta-hydroxybutyrate level, regardless of the source, isindicative of a state of nutritional ketosis with all of its normallyascribed health benefits which is simply not true as will be discussedlater.

For the purposes of the present invention the molecules acetoacetate andacetone will be referred to as ketones as will any other moleculemeeting the chemical definition of a ketone while the moleculebeta-hydroxybutyrate will be referred to as a carboxylic acid due to itschemical structure and function.

As previously mentioned, when ketone production occurs acetoacetate isthe very first ketone produced and has three fates: 1)—Conversion toacetyl-CoA and entry into the citric acid cycle for energy production,2)—spontaneous decomposition to the ketone acetone, and 3)—reversibleconversion to the carboxylic acid beta-hydroxybutyrate in the presenceof D-beta-hydroxybutyrate dehydrogenase when cellular NADH levels arehigh. Important to note here is that of the three, only acetoacetate andbeta-hydroxybutyrate have significant value for energy production in thebody. Further, only acetoacetate is a substrate for conversion toacetyl-CoA which enters the citric acid cycle as there is nointerconversion between beta-hydroxybutyrate and acetyl-CoA and unlessbeta-hydroxybutyrate can become acetoacetate it holds no value forenergy production.

For the purposes of the present invention the described relationshipbetween acetoacetate and beta-hydroxybutyrate cannot be emphasizedenough and this is due to the fact that only endogenous production oftrue ketones occurring within the liver secondary to the breakdown ofthe body fat facilitates weight loss with improvements in lipid profile.

For the purposes of the present invention a ketogenic state refers to ametabolic state wherein the liver produces ketones from fatty acidoxidation for energy purposes. Once acetoacetate has been produced inthe liver a portion of it is converted to beta-hydroxybutyrate andacetone and these substances are released into the blood. As more andmore acetoacetate, acetone, and beta-hydroxybutyrate are released intocirculation the concentration of these molecules in the body rises andas state known as ketosis is reached. For the purposes of the presentinvention the terms “ketosis” and “nutritional ketosis” refer to asubject being in a state of endogenous ketone production with elevatedblood levels of ketones in the urine, breath, or blood. Nutritionalketosis is described as a state in which all tissues capable of relyingupon ketones for energy are actively doing so and typically occurs afteran individual has been in a state of ketosis for one or more weeks.There are various conventional ways of measuring if an individual hasentered a state of ketosis and they include analysis of urine, breath,and blood. When ketone production in the liver begins acetoacetate isthe first ketone produced and as this ketone enters the blood it isfiltered by the kidneys and excreted in the urine and easily measured.Therefore, it is conventionally understood that when an individual has aurine acetoacetate concentration of at least 5 mg/dL they are said tohave entered a state of endogenous ketosis. A state of endogenousketosis is also understood to have been reached when the bloodconcentration of beta-hydroxybutyrate rises to at least 0.5 mmol/Lsecondary to acetoacetate production in the liver, not becausebeta-hydroxybutyrate is itself a ketone. Likewise, acetoacetate isspontaneously decarboxylated to acetone and shuttled through the bloodto the lungs for disposal in the breath. Non-ketogenic individualstypically have a breath acetone level of <2 ppm while breath acetonelevels of ≥2-5 ppm indicate endogenous ketogenesis if they occur in theabsence of other potential false positives such as alcohol consumption.For the purposes of the present invention it is assumed that anyacetone, acetoacetate, or beta-hydroxybutyrate present in the breath,urine, or blood at levels indicative of ketosis is secondary to fattyacid oxidation and ketone production in the liver. Of note is thatbecause acetoacetate is the first ketone produced detectibleconcentrations of both acetone and beta-hydroxybutyrate typically lagbehind measurable levels of urinary acetoacetate. This physiologic lagis the very reason that urinalysis for acetoacetate using nitroprussideurine ketone reagent strips is a speedy and inexpensive way to detectinitial entry into ketosis and is the method of detecting entry intoketosis with respect to the present invention.

It is imperative to note here that the state of nutritionally inducedketosis should not be confused with Diabetic Ketoacidosis (DKA). DKA isa state experienced by diabetics who have a high blood concentration ofbeta-hydroxybutyrate from uncontrolled acetoacetate production in theliver with a drop in blood pH secondary to lack of insulin, infection,trauma, or other malnutrition. In contrast to the low bloodbeta-hydroxybutyrate levels experienced in dieting individuals thosesuffering from DKA may have blood beta-hydroxybutyrate levels of 25mmol/L with accompanying electrolyte, pH, and metabolic disturbances.Confusion of DKA with nutritional ketosis is virtually impossible unlessone has an incomplete understanding of either state.

A ketogenic diet is one that is high in dietary fat and low incarbohydrate with only moderate protein intake at 1-2 g/kg of bodyweight per day. Classically, ketogenic diets are composed of 75-85% ofcalories from fat, 15-25% of calories from protein, and 5-10% ofcalories from carbohydrate. Typically ketogenic diets require a dietarycarbohydrate restriction of less than 50 g per day for a number of daysfor individuals to enter a state of sustained nutritional ketosis andutilize their fat stores for fuel. One of the highly researched andwritten about benefits of a ketogenic diet is that it allows anindividual to lose weight from fat while preserving total body proteinstores i.e. muscle tissue. Cox et al, in a paper on exercise performanceand ketosis, concluded that a state of nutritional ketosis had theability to increase anabolic muscle metabolism and recovery in athletessecondary to sparing protein utilization for energy production purposes.The ability to preserve total body protein while losing weight from fathas huge potential over traditional diets as the preservation of proteintypically does not occur in a diet that simply cuts calories or is lowin fat due to protein being converted to glucose for energy. BergsBiochemistry, 5th edition, contains the following statement:

“Even under starvation conditions, the blood-glucose level must bemaintained above 2.2 mM (40 mg/dl). The first priority of metabolism instarvation is to provide sufficient glucose to the brain and othertissues (such as red blood cells) that are absolutely dependent on thisfuel. However, precursors of glucose are not abundant. Most energy isstored in the fatty acyl moieties of triacylglycerols. Recall that fattyacids cannot be converted into glucose, because acetyl-coA cannot betransformed into pyruvate. The glycerol moiety of triacylglycerol can beconverted into glucose, but only a limited amount is available. The onlyother potential source of glucose is amino acids derived from thebreakdown of proteins. However, proteins are not stored, and so anybreakdown will necessitate a loss of function.”

Thus preservation of total body protein can be a state that is conducivenot only to weight loss from actual fat, but also recovery from medicalconditions and surgeries as well as bodybuilding and sports nutrition.Another positive aspect of a ketogenic diet is that due to the highindividual intake of fat and protein satiety is prolonged and hunger isnot experienced while weight loss occurs. This lack of hunger is one ofthe strong points of a ketogenic diet due to the fact that lack ofhunger makes the diet easier to complete than a typical low-calorie, orlow-fat diet. Finally, ketogenic diets themselves have been shown toimprove insulin resistance, improve lipid panel, and facilitate weightloss; all of which contribute to diabetes and metabolic syndrome whendysregulation occurs.

Despite the researched and reported health benefits of the ketogenicdiet the major barrier that prevents individuals from maintaining astate of ketosis long enough to lose significant weight from fat are therequirements for entering ketosis and maintaining ketosis.

Normally, to enter ketosis an individual must restrict carbohydrateintake to 50 g or less per day for a period of time adequate to reduceblood glucose levels and deplete glycogen stores for transition to theproduction of ketones for energy. The length of time required tocomplete the task of entering ketosis is highly variable and dependsupon several factors such as individual glycogen storage capacity,metabolic rate, and exercise. For example, an individual with a lowresting metabolic rate who does not exercise may be required to consume20 g or less of carbohydrate per day to enter ketosis; individuals withhigher metabolic rates may be able to consume more carbohydrate andenter ketosis while completing little or no exercise. Studies concludethat the average American consumes roughly 270 g of carbohydrate perday, although this amount is criticized as being low, in the form ofbreads, pastas, sodas, and other processed food. Therefore, restrictingcarbohydrate intake to 50 g is usually difficult for the average personwith further reductions being much more difficult to achieve. Typically,a person may have to consume this low level of carbohydrate, 50 g or 20g, for two days to a week or more to enter a ketogenic state that can bemeasured via the common methods which are urine, breath, or blood. Thisperiod of carbohydrate reduction with no apparent generation ofmeasurable ketones typically produces hunger, fatigue, light-headedness,and frustration as side effects while the body switches from utilizingglucose to ketones and is the major reason individuals do not adhere tothe ketogenic diet long enough to see any noticeable effect. Symptoms oftransitional hypoglycemia are described as irritability, foggy-thinking,headache, fatigue, and light-headedness and are commonly experiencedbetween day one of a restricted carbohydrate diet and initiation ofketogenesis.

As previously stated this transitional hypoglycemic state may last fordays depending on how fast an individual can enter ketosis. Thus theability for mass numbers of individuals to enter a ketogenic state isseverely retarded by the duration of carbohydrate restriction requiredto enter ketosis and the subsequent perceived difficulties oftransitioning to a ketogenic state. Another perceived difficulty of theketogenic diet is re-entering ketosis after a carbohydrate loading dayor a cheat day. Acute carbohydrate consumption after a carbohydratedepleted state can double an individual's glycogen stores which wouldthen require several days of carbohydrate restriction to re-enterketosis. A similar difficulty is that some individuals will be kickedout of ketosis if they consume just a few grams of carbohydrate overtheir limit required for maintaining ketosis while on the diet itself.

Therefore, a need exists to overcome the problems with the prior art asdiscussed above, and particularly for a more efficient way to enter intoand maintain a ketogenic state.

SUMMARY

This Summary is provided to introduce a selection of disclosed conceptsin a simplified form that are further described below in the DetailedDescription including the drawings provided. This Summary is notintended to identify key features or essential features of the claimedsubject matter. Nor is this Summary intended to be used to limit theclaimed subject matter's scope.

The present invention is directed to a formulation, to an oral dietarysupplement containing a combination of alpha lipoic acid, chromiumpicolinate, L-arginine, and calcium carbonate as active ingredients torapidly induce a state of ketosis when accompanied with moderateexercise and carbohydrate restriction. This rapid induction of ketosisis highly beneficial for transition to a nutritional ketogenic state dueto a shortened transition time. Specifically, the combination in thepresent invention relies upon a synergistic effect to induce a state ofendogenous ketosis through intrinsic action at the cellular level.

The present invention relies upon a combination of alpha lipoic acid,chromium picolinate, L-arginine, and calcium carbonate to induce glucoseuptake and disposal with glycogen depletion via increased GLUT proteinexpression, increased vasodilation, increased ketogenesis, increasedlipolysis, and inhibition of gluconeogenesis and lipogenesis throughmodulation cellular pathways including IRS1, Akt, CBL, AMPK, and MAPK.The net result of the processes mentioned above is such that when thepresent invention is administered and moderate exercise is completedalong with carbohydrate restriction total body glucose and glycogenstores are rapidly depleted resulting in a state of endogenous ketosisin only a few hours.

The present invention is a synergistic combination of alpha lipoic acid,chromium picolinate, L-arginine, and calcium carbonate which can be usedto rapidly induce a state of endogenous ketosis when accompanied withcarbohydrate restriction and exercise in individuals who wish to followa ketogenic diet. This invention will drastically reduce the timerequired to enter an endogenous ketogenic state to only a few hoursafter ingestion as opposed to the normal days to weeks of restrictedcarbohydrate intake making the low-carbohydrate, ketogenic diet easierfor individuals to maintain.

In one embodiment, the present embodiment comprises: about 26.66-28.57percent by mass of alpha lipoic acid; about 0.01-0.02 percent by mass ofchromium picolinate; about 47.61-49.99 percent by mass of L-arginine;and, about 23.33-23.81 percent by mass of calcium carbonate.

In one embodiment, the present embodiment includes a method for inducinga state of endogenous ketosis when accompanied with carbohydraterestriction by a user. The method includes restricting carbohydrateconsumption; and, consuming a composition comprising: about 26.66-28.57percent by mass of alpha lipoic acid; about 0.01-0.02 percent by mass ofchromium picolinate; about 47.61-49.99 percent by mass of L-arginine;and, about 23.33-23.81 percent by mass of calcium carbonate. In oneembodiment, carbohydrate restriction is in a maximum dosage of about 20grams per day. Additionally, in one embodiment, the method is furtheraccompanied with moderate exercise.

To the accomplishment of the above and related objects, this inventionmay be embodied in the form illustrated in the accompanying drawings,attention being called to the fact, however, that the drawings areillustrative only, and that changes may be made in the specificconstruction illustrated and described within the scope of the appendedclaims. The foregoing and other features and advantages of the presentinvention will be apparent from the following more particulardescription of the preferred embodiments of the invention, asillustrated in the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute partof this specification, illustrate embodiments of the invention andtogether with the description, serve to explain the principles of thedisclosed embodiments. The embodiments illustrated herein are presentlypreferred, it being understood, however, that the invention is notlimited to the precise arrangements and instrumentalities shown,wherein:

FIG. 1 is a perspective view of the molecular structure of Racemic R/SAlpha Lipoic Acid, according to an example embodiment;

FIG. 2 is a perspective view of the molecular structure of ChromiumPicolinate, according to an example embodiment;

FIG. 3 is a perspective view of the molecular structure of L-arginine,according to an example embodiment; and,

FIG. 4 is a perspective view of the molecular structure of CalciumCarbonate, according to an example embodiment;

DETAILED DESCRIPTION

The following detailed description refers to the accompanying drawings.Whenever possible, the same reference numbers are used in the drawingsand the following description to refer to the same or similar elements.While disclosed embodiments may be described, modifications,adaptations, and other implementations are possible. For example,substitutions, additions or modifications may be made to the elementsillustrated in the drawings, and the methods described herein may bemodified by substituting reordering, or adding additional stages orcomponents to the disclosed methods and devices. Accordingly, thefollowing detailed description does not limit the disclosed embodiments.Instead, the proper scope of the disclosed embodiments is defined by theappended claims.

The disclosed invention includes a composition and methods for rapidlyinducing a state of measurable endogenous ketosis. The present inventionprovides a physical and psychological stepping stone to maintaining aketogenic state through carbohydrate restriction and exercise.

The present invention relates to an oral dietary supplement containing acombination of alpha lipoic acid, chromium picolinate, L-arginine, andcalcium carbonate as active ingredients to rapidly induce a state ofketosis when accompanied with moderate exercise and carbohydraterestriction. This rapid induction of ketosis is highly beneficial fortransition to a nutritional ketogenic state due to a shortenedtransition time. Specifically, the combination in the present inventionrelies upon a synergistic effect to induce a state of ketosis throughintrinsic action at the cellular level.

A ketogenic diet is required to maintain a ketone producing state whichrelies upon metabolism of stored fat for energy production whilepreserving muscle mass. The present invention is such that it allows forrapid induction into ketosis as opposed to the normally required days toweeks of severely reduced or restricted carbohydrate intake. For thepurposes of the present invention the term “rapid” as used herein refersto inducing a state of ketosis, in an individual, in only a few hours.The above described rapid induction to ketosis happens due to that factthat ketone production hinges on the bodies current carbohydrate state,loaded or depleted. In a normal individual, if the body's carbohydratestores i.e. glycogen and glucose are at maximum capacity there will beno ketogenesis. If dietary carbohydrate is restricted, blood glucose islowered, and glycogen stores are depleted without being replenished theresult is that cells must now rely on an alternative source of fuelwhich is fat with subsequent ketone production.

The generalized mechanism of the present invention is activation ofmultiple cellular pathways that result in increased glucose and glycogendisposal and depletion, lipolysis, fatty acid oxidation, and inhibitionof gluconeogenesis and lipogenesis to arrive in a state of endogenousketone production. However, it is currently understood and accepted thatall mechanisms of cellular metabolism have not been fully elucidated,and not wishing to be bound by any particular theory it is believed thatthe present invention will function through the interaction of severalcomplementary mechanisms which are outlined below and which areintrinsic properties of the inventions individual components in thefollowing ways:

Referring to FIG. 1, FIG. 1 is a perspective view of the molecularstructure of Racemic R/S Alpha Lipoic Acid, according to an exampleembodiment. Alpha lipoic acid (ALA), or 1, 2-dithiolane-3-pentanoicacid, is a naturally occurring dithiol compound synthesizedenzymatically in the mitochondrion of cells from octanoic acid. AlphaLipoic acid is a necessary cofactor for mitochondrial alpha-ketoaciddehydrogenases and energy production and metabolism in the body. Alphalipoic acid has two enantiomers, R and S, with the R enantiomer thoughtto be more absorbed and active than the S enantiomer, however, the Renantiomer is unstable without the S enantiomer present. Reports areavailable which indicate that supplements composed of the stabilized Renantiomer only are more expensive than racemic mixtures, possibly notas pure as claimed, and may have lower absorption therefore a racemicmixture of R and S alpha lipoic acid is utilized for the presentinvention. Alpha Lipoic acid in a racemic mixture of R and Senantiomers, when taken orally, has roughly a 30% bioavailability afterabsorption, and has been shown to have a half-life of thirty minutes toone and one half hours with complete plasma clearance in approximatelythree hours. In studies where individuals with impaired insulinsignaling cascades received 600, 1200, and 1800 mg daily for four weeksthe effectiveness of the signaling cascade on glucose uptake andutilization improved 25% and the effect of glucose uptake in individualswith intact insulin signaling cascades is even higher. The effect ofsupplementation of ALA is to promote reductions in blood glucose throughactivation of multiple cellular proteins such as IRS1, Akt, CBL, AMPK,and MAPK in the insulin receptor signaling cascade which increaseglucose uptake and disposal. This modulation of the insulin signalingpathway induces cells to express proteins known as glucose transporters,i.e. GLUT proteins, on the cellular surface. Several types of GLUTproteins exist and are identified by number GLUT1, GLUT2, GLUT3 . . .etc. GLUT is found in highest concentrations in red blood cells and onthe blood-brain barrier, GLUT2 in the liver, GLUT3 on neurons, and GLUT4is found primarily on skeletal muscle cells. GLUT proteins function tolower blood glucose by allowing the passage of glucose into the cell tobe metabolized. GLUT2 and GLUT3 proteins are insulin independenttransporters. GLUT1 proteins are insulin independent, but insulin canincrease their expression on the cellular surface; GLUT4 proteins areonly expressed with activation of the insulin pathway or transientlyactivated with exercise. However, alphalipoic acid was found to induceexpression and activation of GLUT1 and GLUT4 proteins independent ofexercise or presence of the hormone insulin by activating the downstreaminsulin signaling pathway resulting in increased glucose uptake. Thebioactive half-life of endogenously synthesized insulin has beenreported to be approximately 5-10 minutes and in the absence of insulinpathway activation or exercise GLUT4 proteins are not expressed oncellular surfaces and are sequestered inside of the cell within storagevesicles.

The present invention induces GLUT1 and GLUT4 protein mediated glucoseuptake by activating the downstream insulin signaling pathway via itsalpha lipoic acid component, and due to the 1-3 hour action of alphalipoic acid GLUT proteins may be expressed for extended periods of time,with or without exercise, leading to 40-80% increases in glucose uptakeand disposal. In addition to increasing GLUT protein expressionactivation of cellular AMPK itself, by alpha lipoic acid, has been shownto stimulate ketogenesis, lipolysis, and fatty-acid oxidation whileinhibiting lipogenesis and gluconeogenesis. By inhibitinggluconeogenesis in the liver, no new glucose can be produced from aminoacids or protein catabolism which further contributes toglucose/glycogen depletion and an increased ketogenic state. Although anormal diet contains small amounts of ALA only small amounts can beabsorbed in the free form from the diet, and further the amounts of ALAabsorbed can be channeled to other pathways of metabolism by the bodyinstead of promoting glucose uptake. By lowering blood glucose andexpending glycogen stores, ALA has the potential to induce a ketogenicstate in only a few hours when supplemented in adequate amounts andaccompanied with moderate exercise and carbohydrate restriction. WhileALA has the capacity to deplete glycogen and glucose over timeindependent of exercise, it is suggested that exercise be completed dueto its additive effect at increasing GLUT protein expression which aidsin decreasing the time needed to arrive in ketosis.

Referring to FIG. 2, FIG. 2 is a perspective view of the molecularstructure of Chromium Picolinate, according to an example embodiment.Chromium is a mineral that is required by humans for normal cellularenergy metabolism. Two major forms of chromium exist trivalent (III) andhexavalent (VI) with the hexavalent form being toxic in humans.Trivalent forms of chromium include chromium nicotinate, chromiumpicolinate, chromium chloride, chromium polynicotinate, and chromiumenriched yeast. Chromium is poorly absorbed, only about 1-2% of aningested dose, and has been shown to have complete plasma clearancehalf-life 8-12 hours. Supplementation of chromium has been found toincrease the rate of cellular glucose uptake several times normal withand without the presence of insulin or exercise through increased GLUTprotein expression on muscle cells. Further observation has shown thatthe effect of chromium supplementation is activation of key proteinssuch as IRS1, Akt, CBL, AMPK, and MAPK, within the cell, located at anddownstream of the insulin receptor; as chromium, much like lipoic acid,can act to induce increased GLUT protein expression, especially skeletalmuscle GLUT4, while promoting ketogenesis, lipolysis, beta-oxidation andinhibiting gluconeogenesis, and lipogenesis.

Referring to FIG. 3, FIG. 3 is a perspective view of the molecularstructure of L-arginine, according to an example embodiment. L-arginine,an α-amino acid, is one of the twenty most common amino acids in nature.Arginine is a conditionally essential amino acid due to the fact that itis not biosynthesized in sufficient quantities under normal conditionsand is required for a limited number of metabolic reactions. Scenariosin which arginine becomes essential occur when the body's metabolism issped up due to recovery from illness, weight loss, and anabolic musclemetabolism. Arginine is the immediate precursor to the potentvasodilator nitric oxide which exerts its effects by relaxing smoothmuscle surrounding vascular tissue which results in an increased bloodflow without increased blood pressure. Secondary to the increased bloodflow mediated by nitric oxide is the increased delivery of nutrients tocells primarily in the form of glucose and amino acids for carbohydrateand protein metabolism. Contrary to popular belief, L-arginine has notbeen shown to increase the synthesis of nitric oxide during exercise andthis is thought to be due to the myriad of vasodilator mechanismsalready in operation in tissues during normal exercise. However,L-arginine has been shown to increase nitric oxide synthesis in restingtissues with subsequent vasodilation effects which increase nutrientdelivery to tissues over time. The importance of increased vasodilationduring rest cannot be stressed enough as it is an integral part of thepresent inventions mechanism of action. Exercising muscle tissue hasbeen shown to have increased glucose uptake via GLUT4 proteinsindependent of insulin, but insulin is required for glucose uptake inresting muscle tissue. However, alpha lipoic acid and chromium mediateglucose uptake via GLUT1 and GLUT4 protein expression during periods ofexercise and rest regardless of the presence of insulin and anyvasodilation secondary to increased nitric oxide production fromL-arginine supplementation that permits delivery of more glucose tocells from increased blood flow, at rest, speeds the glucose/glycogendisposal process itself. Along with increasing cellular glucose uptakealpha lipoic acid and chromium have both been shown to catalyze nitricoxide dependent vasodilation via increased expression of endothelialnitric oxide synthase (eNOS), the enzyme directly responsible for nitricoxide production from L-arginine.

Referring to FIG. 4, FIG. 4 is a perspective view of the molecularstructure of Calcium Carbonate, according to an example embodiment.Calcium Carbonate is included in the present invention and has a dualrole. First, calcium carbonate may act as a gastric acid bufferingredient as heartburn may be experienced with supplementation of anyamount of alpha lipoic acid. Further, calcium is required by smoothmuscle cells as a mediator in the pathway of nitric oxide smooth musclerelaxation before vasodilation occurs and multiple sources estimate thattwo-thirds of Americans may be calcium deficient.

It is possible for an individual to reach ketosis quickly by exercisingcontinuously for a sufficient length of time. An individual can greatlyreduce their muscle glycogen stores after 90-120 minutes of continuoushigh intensity exercise, such as running, and without carbohydrateconsumption ketosis will eventually ensue when body glycogen isexhausted. 90-120 minutes is roughly half the time it takes a trainedrunner to complete a full marathon and because of this, runnerstypically have a carbohydrate loading day before a marathon in whichcarbohydrate consumption doubles their normal muscle glycogen storesallowing them to perform at high levels for extended periods of timewithout fatigue. It has been shown that the muscles of trained vs.untrained individuals store different amounts of glycogen. In the SportsNutrition Guide Book it is outlined that 100 g of untrained muscletissue can store roughly 13 g of glycogen whereas 100 g of trained orcarbohydrate loaded muscle tissue may store 32-40 g of glycogen and thatthese stores can be depleted quickly through exercise.

For most individuals running continuously for 90-120 minutes isphysiologically impossible for multiple reasons including current billof health, age, state of overall fitness, or just pure lack of time.Highly variable studies have been conducted into the rate of glycogenutilization in tissues based on the amount of time exercised and oxygenconsumed during exercise. VO2 max is a measurement of the maximum volumeof oxygen an individual can consume during exercise and is related toheart rate and ability to oxidize fuels for energy production; the moreconditioned an individual is the higher their VO2 max. Skeletal muscleglycogen stores have been found to be three-fourths depleted afterintense exercise, 85-90 minutes with continuous cycling at 70-90% VO2max, resulting in an oxidation of roughly 1-3 g of muscle glycogen perminute in untrained and trained individuals respectively. It has alsobeen shown that exercise at a low VO2 max of 41% for 60 minutes resultedin complete glycogen depletion in type 1 muscle fibers and 20% depletionin type 2A muscle fibers; indeed completing some form of moderateexercise for roughly twenty minutes has been shown to decrease overallmuscle glycogen stores by one-fifth and as muscle glycogen is graduallydepleted muscles become fatigued and begin to rely on liver glycogen andglucose to meet energy needs.

Resting muscle cells typically rely on a ratio of carbohydrate and fat,and during exercise this ratio becomes unbalanced as 70-85% of energyproduction is from glycogen alone which results in rapid glycogendepletion if carbohydrates are not consumed. It is widely held that fatis the source of fuel when not exercising or exercising at lowpercentages of VO2 max and when an individual exercises at 55-75% oftheir VO2 max glycogen utilization and disposal are at maximum. The VO2max for an average individual is between 26-52 ml.kg-1.min-1 and for theaverage individual exercising at 50-70% of VO2 max constitutes joggingor running. As exercising muscles burn through their glycogen storesthey express GLUT4 proteins which increase the uptake of glucose fromthe blood and these proteins are expressed as long as exercise isoccurring and a need for glucose is present. Richter et al found thatincreasing exercise intensity increased the number of GLUT4 proteinsexpressed on cellular surfaces which increased the uptake of glucose.Richter further found that glucose uptake and GLUT4 expression inexercising muscle tissue could be enhanced by independent activation ofthe insulin signaling pathway through modulation of proteins such asIRS1, Akt, CBL, AMPK, and MAPK, the same proteins activated by alphalipoic acid and chromium.

As previously mentioned the liver functions as a total bodyglucose/glycogen reserve with a glycogen storage capacity of about90-110 g, yet this amount of glycogen does not yield sufficient glucoseto maintain normal blood glucose levels as well as supply glucose to thebrain, red blood cells, and muscles for extended periods of time.Indeed, it has been stated that roughly twenty minutes of continuousexercise has the capacity to reduce muscle glycogen by one-fifth andeven the loss of one-fifth of total body muscle glycogen throughexercise is more than the liver has the capacity to restore ifcarbohydrates are not consumed shortly after exercise.

It is therefore believed that fastest way reach an endogenous ketogenicstate is to empty the liver of its glycogen stores by facilitatingglucose and glycogen disposal in skeletal muscles through induced andincreased GLUT protein expression and when the liver has beensufficiently depleted of its glycogen it begins to oxidize fatty acidsfor energy with the subsequent production of ketones which then can beused for fuel. In addition, the activation of pathways involved inlipolysis and beta-oxidation promote lipid mobilization from adiposetissue to be used for energy production. Finally, the inactivation ofgluconeogenic and lipogenic pathways prevents the formation of any newglucose or lipid within the body.

The present invention relies upon a combination of alpha lipoic,chromium picolinate, L-arginine, and calcium carbonate to induce glucoseuptake and disposal with glycogen depletion via increased GLUT proteinexpression, increased vasodilation, increased ketogenesis, increasedlipolysis, and inhibition of gluconeogenesis and lipogenesis throughmodulation cellular pathways including IRS1, Akt, CBL, AMPK, and MAPK.The net result of the processes mentioned above such that when thepresent invention is administered and moderate exercise is completedalong with carbohydrate restriction total body glucose and glycogenstores are rapidly depleted resulting in a state of endogenous ketosisin only a few hours.

The term “about” or “approximately” as used herein refers to beingwithin an acceptable range for the particular value as determined by oneof ordinary skill in the art. The term “about” can mean within one ormore standard deviations, within one or more percents, or within one ormore orders of magnitude. Where individual values are described in thespecification and claims the term “about” is interpreted as being withinan acceptable range for the particular value.

Concentrations, amounts, solubilities, and other numerical data may beexpressed or presented herein in a range format. It is understood thatsuch a range format is used for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that range.As an illustration, a numerical range of “about 1 to about 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include the individual values and sub-ranges withinthe indicated range.

As previously mentioned, for purposes of the present invention the terms“Ketosis” and “nutritional ketosis” as used herein refer to a subjectbeing in a state of endogenous ketone production with ketoneconcentration measurable through breath, urine, or blood testing.Further, for the purposes of the present invention entry into a state ofketosis is designated as an individual having a measurable urine ketonelevel of at least 5 mg/dL of acetoacetate. It was previously stated that5 mg/dL of urinary acetoacetate, 0.5 mmol/l of bloodbeta-hydroxybutyrate, or ≥2 ppm of breath acetone are all indicators ofentry into ketosis. However, the purpose of the present invention is torapidly induce an easily measured state of ketosis and the easiest wayto measure entry into an endogenous ketogenic state is urinalysis forthe ketone acetoacetate and this is because measurable amounts ofbeta-hydroxybutyrate and acetone may lag behind measurable acetoacetatelevels and require additional equipment for blood and breath analysis.Further the correlation between urine acetoacetate, bloodbeta-hydroxybutyrate, and breath acetone is not always clear as thelevels of each may be affected by hydration, acid-base balance, andrenal function. As previously stated, for the purposes of the presentinvention, 5 mg/dL of urinary acetoacetate as detected usingnitroprusside reagent strips which detect only the ketone acetoacetateis the recommended method for detection of entry into ketosis becausethe test is accurate, simple to complete, inexpensive, and widelyavailable.

The term “preferred” as applied to embodiments found herein describesthe embodiment that is most suited for use by the majority of subjectsdue to various qualities such as ease of use, size of dose, route ofadministration, and efficacy at inducing the desired effect.

It is to be understood that various embodiments of the present inventionmay be produced without departing from the scope of the invention ifthey promote the mechanism of the invention by modulating the previouslyoutline pathways and result in the desired effect, for example:L-citrulline is a direct precursor to L-arginine and studies haveindicated that L-citrulline supplementation can increase L-arginineblood levels to a greater degree than L-arginine supplementation itselfdue to L-citrulline being taken up by the kidney and converted directlyto L-arginine. The enzyme arginase is present in the liver and is highlyactive in metabolizing any entering L-arginine to urea which effectivelyreduces the amount of L-arginine available for nitric oxide production,however this does not occur with L-citrulline supplementation. The aminoacid L-citrulline also has a salt form known as citrulline malate inwhich the malic acid portion enhances the effect of L-citrulline byincreasing its absorption as well as promoting enhanced energyproduction in exercising muscle via exerting effects on the citric acidcycle. It is therefore understood that because L-citrulline andcitrulline malate are direct precursors to L-arginine they may besubstituted in the place of L-arginine if a different embodiment isdesired without deviating from the proposed mechanism of nitric oxidemediated vasodilation. However, the effect of utilizing L-citrulline orcitrulline malate to increase available L-arginine for subsequent nitricoxide production purposes can be dampened by the presence of variousstates of kidney disease, altered amino acid metabolism, or sheer amountrequired to produce the desired effect and as such they are not includedin the preferred embodiment. Also, as mentioned previously, trivalentchromium moieties include chromium nicotinate, chromium picolinate,chromium chloride, chromium polynicotinate, and chromium enriched yeastand any of these compounds may be substituted interchangeably if adifferent embodiment is desired as they all exert the same effect on theIRS1, Akt, CBL, AMPK, and MAPK pathways, however the preferredembodiment contains chromium picolinate as the trivalent chromiummoiety.

In any embodiment of the present invention the preferred route ofadministration is oral. The product may be delivered as a powderedmixture, a pre-mixed drinkable liquid, tablet, gelatin capsule,concentrated gel, or any other dosage form known to those trained in theart. The preferred embodiment of the present invention includes acombination of alpha lipoic acid, chromium picolinate, L-arginine, andcalcium carbonate comprised of the following ranges of minimum weightsand percents and is delivered as an orally supplemented capsule(s):

-   -   Alpha lipoic acid: 600-800 mg    -   Chromium picolinate: 200-500 mcg    -   L-arginine: 1000-1500 mg    -   Calcium carbonate: 500-700 mg    -   Total weight: 2100.2-3000.5 mg    -   Minimum percent:    -   Alpha lipoic acid: 26.66-28.57%    -   Chromium picolinate: 0.01-0.02%    -   L-arginine: 47.61-49.99%    -   Calcium carbonate: 23.33-23.81%

Production.

Any embodiment of the present invention is compounded by mixing therequired amounts of each ingredient in such a way that is suitable forthe desired delivery method whether that be powdered mixture, apre-mixed drinkable liquid, tablet, gelatin capsule, concentrated gel,or any other dosage form known to those trained in the art. Suchembodiments may contain sweeteners, flavoring agents, coloring agents,preservatives, pharmaceutically acceptable excipients, binding agents,or lubricating agents pertaining to the delivery method desired.

Use.

The term “Administration” is defined as the process in which any of thedescribed embodiments of the present invention are delivered to anindividual. Routes of administration include oral, intragastric, andparenteral. Administration of the present invention will often depend onthe number of doses required to reach ketosis. One “dose” defined as theamount of any single embodiment that is sufficient to induce a state ofendogenous therapeutic ketosis in the average individual. The number ofadministered doses required to reach ketosis may vary depending onindividual weight, age, sex, duration of exercise, individual metabolicrate, and individual glycogen storage capacity.

The term “individual” is understood to encompass any member of theanimal kingdom, but for the purposes of the present invention individualrefers most appropriately to a human being. As used herein the term“patient” is interchangeable with “subject”.

In a non-limiting example of use, an individual wishing to rapidly entera state of ketosis may make use the present invention in the followingmanor:

-   1. On the day an individual desires to enter a ketogenic state the    individual begins by restricting dietary carbohydrate as much as    possible, preferably to less than 20 g.-   2. The individual self-administers one dose of the present invention    on an empty stomach.-   3. Thirty minutes after administration the individual performs    moderate intensity exercise.-   4. Three hours after administration the individual uses    nitroprusside urine ketone reagent strips to test for the presence    of the ketone acetoacetate in the urine.-   5. If the individual's urinalysis is negative for ketone production    three hours after administration of the first dose, a second dose is    self-administered.-   6. Beginning one hour after administration of a second dose the    individual uses nitroprusside ketone reagent strips to randomly test    for entry into ketosis as confirmed by a positive test.

Advantages.

The present invention is useful as it would allow a significantly largernumber of individuals to rapidly and easily enter a ketogenic statetherefore increasing their potential to lose weight and reap the healthbenefits of the ketogenic diet itself. 2012 statistics on the diet andweight loss supplement industry are as follows: 20 billion dollars inannual revenue were generated, 108 million people in the U.S. were onsome form of diet, and 220,000 morbidly obese individuals underwentgastric bypass surgery (2009) with an $11,000-$26,000 cost per gastricbypass surgery. In 2014 the diet industry revenue was estimated to bebetween $20-$40 billion and surpass $60 billion by 2021. In February2015, Wall Street Journal ran an article on the value of AtkinsNutritionals, a low-carbohydrate food producing company that was on themarket for sale. In the article, the Journal estimated that AtkinsNutritionals would fetch more than $1 billion in a sale to anothercompany. Research shows that there is a huge market for a dietarysupplement that would allow rapid entry into a true endogenous ketogenicstate, especially if it does not rely upon the current mechanisms ofavailable diet supplements and has a limited side effect profile both ofwhich make the present invention novel as compared to other supplementsin general and ketogenic supplements specifically. Indeed it has beenpreviously estimated that at least 17.2% of American households containat least one individual on a low-carbohydrate, ketogenic diet and atleast 19.2% of Americans have attempted a low-carbohydrate, ketogenicdiet. Considering the current lineup of diet industry supplements forweight loss and as well as the ketogenic supplement niche, the presentinvention is novel for a least the following reasons:

-   A. Unlike other dietary supplements for weight loss the present    invention does not claim torequire any additional dietary    consumption of carbohydrates, lipids, proteins, ketones, or    stimulants to induce ketosis.-   B. Unlike other dietary supplements for weight loss developed and    marketed because they contain stimulants such as caffeine, green    coffee bean, green tea, or synephrine that act to modulate nervous    system output the present invention does not contain any stimulant    nor does it induce symptoms of excess nervous system stimulation    such as tachycardia, tachypnea, diaphoresis, nausea, vomiting, or    fever.-   C. Unlike other dietary supplements for claim to help stabilize    blood glucose in healthy and/or diseased adults the present    invention does not claim to stabilize blood glucose levels. In fact,    the preset invention makes use of a mechanism to deplete blood    glucose and glycogen to a level adequate for ketone generation,    normally between 60-80 mg/dl of blood glucose.-   D. Unlike other dietary supplements for weight loss that claim to be    fat burners the present invention has no intrinsic mechanism to burn    fat itself.-   E. Unlike other dietary supplements in the same field labeled as    “appetite suppressants”, the present invention makes no claim to    suppress, alter, or induce appetite in any way.-   F. The present invention when used as directed for rapid induction    to ketosis is not intended to be a daily dietary supplement. In    fact, the present invention only claims to induce a state of ketosis    rapidly when taken as directed whereupon the individual making use    of the present invention no longer need continue supplementation if    they follow a nutritional ketogenic diet. However, due to the    present inventions ability to turn on specific pathways that promote    glucose and glycogen disposal it is understood that the inventions    use is not limited to induction of ketosis only and could    theoretically be used repeatedly by an individual to help maintain a    state of ketosis.-   G. The present invention due to its ability to rapidly induce    ketosis via glucose and glycogen disposal allows the dieter to have    an occasional cheat day and not jeopardize their diet due to the    fact that they can easily transition back to a ketogenic state and    this type of flexibility allows the dieter to transition to a    ketogenic lifestyle where they are in a state of ketosis the    majority of the time.-   H. Unlike other dietary supplements in the same field that claim to    be carbohydrate blockers, the present invention makes no claim to    block or stop the metabolism of carbohydrates in any way when    carbohydrates are consumed as in a usual, carbohydrate rich diet.    Consumption of excess carbohydrate will override the mechanism of    the present invention to induce ketosis by replenishing glucose and    glycogen stores.-   I. Unlike other dietary supplements in the same field that claim to    be fat blockers, the present invention does not claim to block    dietary fat absorption.-   J. Unlike other dietary supplements of the same field that require    long-term use with multiple stage mechanisms such as “slimming    stages” or “caloric restriction stage” to achieve a goal, the    present invention does not rely upon long-term use with multiple    stages. The present invention is a one-time, or two-time, oral    supplement for rapid induction of ketosis.-   K. The present invention makes no claim to treat any vitamin or    mineral deficiency, disease, or medical illness.-   L. The present invention if used by bodybuilders or fitness    competitors offers a safe alternative to the abuse of diabetic    prescription drugs, such as insulin, for quickly achieving a    ketogenic state or increasing cell volumization through glucose    uptake.-   M. The present invention does not contain any ketones or    beta-hydroxybutyrate nor does it require ingestion of either    substance. Rather, the present invention induces the body to produce    its own ketones endogenously via oxidation of fatty acids in the    liver.-   N. Because the present invention makes the claim to induce ketosis    and yet contains no ketones or beta-hydroxybutyrate it stands alone    as a ketogenic dietary supplement and starkly contrasts the    currently marketed ketogenic diet supplements due to the fact that    they contain some form of ketone, beta-hydroxybutyrate or a salt    thereof, or a ketone-ester and require repeat or daily ingestion.-   O. Because the present inventions mechanism is such that it claims    to rapidly induce ketosis, individuals wishing to monitor their    entry into ketosis can do so inexpensively through the use of    nitroprusside urine ketone reagent strips sold over the counter at    any pharmacy. The ability to visually reaffirm entry into ketosis    via color change on ketone urine test strips promotes diet    compliance.

Endogenous Ketone Production vs. Ketone, Beta-Hydroxybutyrate Salt, orKetone-Ester Supplementation.

The difference between an endogenous ketosis secondary to fatty acidoxidation occurring within the liver and supplementation of ketones,ketone esters, or carboxylic acids such as beta-hydroxybutyrate or asalt thereof deserves further attention. A stark contrast exists betweenthe mechanism of the present invention and supplements today that areproduced or marketed for their claimed effects such as inducing ketosis.The term ketosis as previously given was defined as an elevated level ofketones in the body secondary to endogenous ketone production within theliver from fatty acid oxidation. It would seem that this definition hasbeen misconstrued to mean elevated levels of ketones in the bodyregardless of the source of the ketones. More specifically, elevatedlevels of acetoacetate or acetone after oral supplementation ofbeta-hydroxybutyrate or its salt form or a ketone ester. Recall thatacetoacetate produced in the liver is converted to beta-hydroxybutyratevia the action of D-beta-hydroxybutyrate dehydrogenase when cellularNADH levels are high and this reaction is reversible. Also, aspreviously stated, beta-hydroxybutyrate only has energy value if it canbe re-converted to acetoacetate. This described reversible action of theD-beta-hydroxybutyrate dehydrogenase enzyme is exactly the reason early20th century investigators found acetone and acetoacetate in the breathand urine of those subjects who were given beta-hydroxybutyrate orally,indeed it is a normal and expected finding. It is for such reasons thatcomparing a ketosis secondary to supplementation of ketones,beta-hydroxybutyrate, or ketone esters to a ketosis secondary tohepatic-oxidation of fatty acids is a scenario which can only bedescribed as the spirit of the law vs. the letter of the law.Technically, one could call both states ketosis as levels of ketoneswill be elevated, however the metabolic difference between an exogenousketosis and an endogenous ketosis is astronomical.

The loss of body fat and the improvement in lipid profile is not seenwith supplementation of exogenous ketone sources or beta-hydroxybutyratesalts due to the fact that supplemented ketones or beta-hydroxybutyratesalts have not been derived from acetoacetate secondary to actual fatmetabolism occurring within the body. Effects of supplementation ofbeta-hydroxybutyrate salts were shown in a 2016 publication on thesubject in which Dawley rats were given beta-hydroxybutyrate salts dailyfor 28 days and several health parameters were monitored includingweight, lipid profile, and blood glucose. The study concluded thatsupplemented beta-hydroxybutyrate salts or ketone-esters had no effecton triglycerides or total cholesterol and after four weeks of repeateddaily ingestion. Further, the same study found that orally supplementedbeta-hydroxybutyrate salts or ketone-esters improved blood glucosenumbers, but had no effect to promote weight loss and these findings aremost likely attributed to their being an alternative available source ofenergy through conversion to acetoacetate even though glucose is presentand glycogen is at maximum capacity. The study concluded thatsupplementation of beta-hydroxybutyrate salts or ketone-esters increasesthe blood level of beta-hydroxybutyrate, acetoacetate, and acetone insubjects—again a natural finding. Further the supplementation ofbeta-hydroxybutyrate salts or ketone-esters has been shown to onlyelevate blood levels beta-hydroxybutyrate, acetoacetate, or acetone for6-8 hours after which further supplementation is required and is a farcry from the continuous production of ketones in the liver in anendogenous ketogenic state.

Through extrapolation of these facts it can clearly be seen that anexogenous state of ketosis can be induced in a subject. However thequestion should be posed that if an exogenous ketosis is induced throughoral beta-hydroxybutyrate salts or ketone esters being metabolizeddirectly into acetoacetate what health benefit is conveyed overendogenous ketone production? It can be argued from a valid scientificstandpoint that the reason ketogenic diets are so appealing is becauseof their research proven health benefits such as weight lossspecifically from fat and improved lipid profile and these benefits areonly seen when ketone production occurs within the body and not fromsupplementation. Therefore claims of achieving a nutritional ortherapeutic ketosis via supplementation of ketones, ketone precursors,or beta-hydroxybutyrate are misleading because they insinuate a clearhealth benefit of the same magnitude as an endogenous ketosis and yetprovide none. It is theoretically possible that the supplementation ofbeta-hydroxybutyrate salts or ketone esters has the capacity to affectseizure threshold, but further studies are indicated as there areseveral conflicting ideas as to which molecule actually exerts an effecton the seizure threshold itself—acetoacetate, acetone, orbeta-hydroxybutyrate and how the molecule should be administered.

It is for these reasons that the present invention has a clear advantageover other ketone, ketone-ester, or beta-hydroxybutyrate salt containingsupplements as the present invention does not contain any exogenousketone nor does it contain beta-hydroxybutyrate or its salt form and yetthe present invention induces an endogenous ketogenic state in less thana day.

Research into Ketogenic Mechanisms.

A search in PubMed, the U.S. National Library of Medicine, and NationalInstitutes of Health returns two relevant results for “ketogenic dietpill” which are scientific, peer reviewed, publications: “The ketogenicdiet in a pill: is this possible?” and “Anticonvulsant properties of anoral ketone ester in phentylenetetrazole-model of seizure.”

The first article examines various novel ways of attempting to induceketosis in individuals for neuroprotective purposes that include:modulation of the neurotransmitter GABA, supplementing ketone bodiesdirectly, mitochondrial manipulation, decreasing reactive oxygenspecies, enhancing glutathione to scavenge free radicals, reducingglycolysis by restricting calories, modulating the fat hormone leptin,and supplementing polyunsaturated fats. After discussing each of theabove categories the article concluded: “So the question remains, canthe KD (ketogenic diet) be packaged into a pill? At this stage, givenour state of knowledge, the likely answer is no.” This article waspublished in 2009 by Rho et al. The second publication, from 2015,examines the effectiveness of a ketogenic diet on the treatment ofseizure disorder by supplementing ketone esters. However, the conclusionto the article gives the status quo of scientific research on aketogenic diet pill by stating: “This result suggests that ketone estersmay pave the road towards the establishment of a ketogenic diet in apill.” This language clearly indicates that a pill which would promotean endogenous ketogenic state had not been produced as of that time.

Epilepsy Today, an online information website for education on Epilepsyran an article in 2015 entitled: “Ketogenic pill to treat drug-resistantepilepsy.” This article chronicled recent neuroscience research intousing the drug stiripentol to mimic a ketogenic state which affectsneuronal enzymatic activity in the brain and seems to be an emergingtreatment for seizure disorder.

Clearly from the information provided in these resources a ketogenicdiet pill would be useful in that it would have the ability to affectdisease processes and such a pill is currently being sought for the samereason. However, to date, scientific research has been unable to producean actual ketogenic pill that is efficacious at inducing endogenousketone production without unwanted or harmful side effects and whichprovides all the benefits of the ketogenic state.

The present invention does not rely upon metabolic trickery through theuse of prescription drugs to fool the body into believing it is in astate of ketosis. Further, the present invention does not rely upon anyof the mechanisms put forward in the studies listed immediately above aspotential foundations for developing a ketogenic pill. In fact, it couldbe inferred that the above articles teach-away from the mechanism forinducing ketosis described in the present invention through theirexclusion or oversight of additional mechanisms or fields from which aketogenic diet pill could potentially arise.

Safety of Ingredients.

There is no recommended daily allowance for alpha lipoic acid andsupplementation of alpha lipoic acid has been determined to be safe withno widespread serious or life-threatening reactions reported in eitheranimal or human studies with various ranges of intake, even with largedoses or extended use. Reports of rash, hives, and itching have beenassociated with the use of any amount alpha lipoic acid as well astransient nausea, abdominal pain, and malodorous urine. There have alsobeen reports of alpha lipoic acid interfering with biotin absorptionpathways resulting in decreased biotin absorption. Finally, there hasbeen one scientific publication on alpha lipoic acid interacting withthyroid replacement drugs and individuals requiring thyroid hormonereplacement should consider further investigation into the interaction.Alpha Lipoic Acid has also recently been found to be safe for pregnantwomen as a 2014 study on the use of alpha lipoic acid for treatingperipheral neuropathy during pregnancy concluded that alpha lipoic acidexerted no harmful effect on mother or child.

There is currently no recommended daily allowance for chromium, howeverthere are minimum intakes required for normal energy metabolism and theyrange from 25-35 mcg/day for both men and women. The supplementation ofchromium has been considered safe and doses of up to 1000 mcg ofchromium containing supplements have been used without any reportedadverse effects.

A suggested intake, or tolerable upper limit, for L-arginine has notbeen established, but the maximum dose considered safe is 6,000 mg/dayand this supplement would provide 1000 mg per dose.

Calcium carbonate is 40% calcium by weight and the recommended dailyallowance for males and females 18 years and older is 1300 mg/day, whichthis supplement would provide 200-280 mg of elemental calcium per dose.

Testing and Statistics.

Two trials were conducted to examine the time required for the averageindividual to reach a state of endogenous ketosis through dietarycarbohydrate restriction combined with one round of exercise and todetermine whether or not administration of the present invention wasable to speed this process. Ten subjects participated in the first trialand additional sixteen subjects participated in the second trial.

Trial 1 was designed to estimate the average time required to reach astate of endogenous ketosis through dietary carbohydrate restriction andone round of exercise and the trial was used as a benchmark forcomparison to results from trial two. Participants were selected on avolunteer basis with selection and testing occurring duringJuly-September 2015. Participants were of both sexes, ranged in age from28-66, and were screened for current state of health and excluded ifthey had any history of diabetes or kidney disease or were currentlytaking any medication which would register a false positive on urineacetoacetate nitroprusside reagent strips. Leading up to the trial,subjects consumed their normal diet and on the morning of the first dayof the trial subjects completed a urinalysis to ensure they were not ina state of ketosis. No test subjects were found to be in a state ofketosis and all subjects began the test sequence by restricting totaldietary carbohydrate to 20 g or less per day and completing one round ofmoderate intensity aerobic exercise of their choice. Moderate intensityaerobic exercise may mean when a subject is working hard enough to raisethe subject's heart rate and break into a sweat. Moderate exercise maybe walking briskly (3 miles per hour or faster, but not race-walking),water aerobics, low-intensity weight training, bicycling slower than 10miles per hour, tennis (doubles), ballroom dancing, or generalgardening. Subjects completed exercise routines for at least twentyminutes, but subjects were not restricted from exercising longer thantwenty minutes if they wished. After completion of exercise randomurinalysis was conducted to check for the presence of the ketoneacetoacetate which, if present, in concentrations of at least 5 mg/dLindicated a state of endogenous ketosis. When a subject registered apositive urine ketone test the time was recorded and the trial wasconcluded for that subject. Table 1 below details the results from trial1.

TABLE 1 Investigation into the average time needed for subjects to reachketosis through carbohydrate restriction (≤20 g/24 hr) and one round ofexercise. Subject Exercise Time to Time to Number Sex Time (Min) Ketosis(Min) Ketosis (HR) 1 M 40 3135 52 2 F 36 2576 42 3 F 75 3157 52 4 M 353487 58 5 M 83 1786 29 6 M 60 2488 41 7 M 34 1498 24 8 F 25 3225 53 9 F22 4093 68 10 M 60 2178 36 Average 60% Male 47 2762.3 45.5 40% FemaleSummary: The average time required for men and women to enter ketosisthrough restriction of dietary carbohydrate and one round of exercisewas 2762.3 minutes (SD = 803.31), 95% CI [2188, 3337] or 45.5 hours (SD= 13.85), 95% CI [35.79, 55.21] and the average time spent exercisingwas 47 minutes (SD = 21.10).

Trial 2 consisted of a double-blind, placebo controlled study todetermine whether or not the present invention could reduce the time ittook for the average person to enter a state of ketosis based on resultsfrom trial 1. The ten subjects from trial 1 were carried over and anadditional sixteen new subjects participated in trial 2 bringing thetotal to 26 participants. The new subjects were selected during themonths of March and April 2016 and testing occurred during May 2016.Participants were of both sexes, ranged in age from 20-85, and werescreened for a history of diabetes or kidney disease or use of anymedication which would register a false positive on urine acetoacetatenitroprusside reagent strips and were not allowed to participate if theymet any of the criteria for exclusion. Subjects were assigned a numberand randomly allocated to one of two study groups. Once sorted into agroup each participant was randomly assigned to one of twosub-categories: placebo or therapy.

Leading up to the day of the study the subjects were allowed to consumetheir normal diet. On the day of the study subjects began by restrictingdietary carbohydrate as much as possible. All subjects were allowed toeat, but subjects who chose to consume meals consumed 20 g or less oftotal carbohydrate prior to beginning the testing sequence. All subjectsfasted for two hours prior to administration of the placebo or therapyso as to have an empty stomach to increase absorption of the therapy forthe subjects who received it. During the trial period subjects underwenturinalysis multiple times for the presence of ketones utilizingnitroprusside reagent strips which detect the presence of acetoacetatein the urine and a state of ketosis was considered reached when thereagent strips indicated a urinary concentration of least 5 mg/dL ofacetoacetate.

Immediately before beginning the testing sequence an initial urinalysiswas completed to ensure that subjects were not in a state of ketosis andsubjects who were found to be in a state of ketosis were excluded fromparticipating further. After the initial urinalysis was complete theplacebo or therapy was administered orally. The placebo consisted of1000 mg of calcium carbonate. The therapy consisted of an embodiment ofthe present invention containing 800 mg of alpha lipoic acid, 200 mcg ofchromium picolinate, 500 mg of calcium carbonate, and 1000 mg ofL-arginine. Thirty minutes after receiving the placebo or therapysubjects completed one round of moderate intensity aerobic exercise oftheir choice, with the exception of an 85 year old female who completedno exercise. As above, moderate intensity aerobic exercise may mean whena subject is working hard enough to raise the subject's heart rate andbreak into a sweat. Moderate exercise may be walking briskly (3 milesper hour or faster, but not race-walking), water aerobics, low-intensityweight training, bicycling slower than 10 miles per hour, tennis(doubles), ballroom dancing, or general gardening. All exercise routineslasted for a minimum of twenty minutes, however subjects were notdiscouraged from exercising for longer than twenty minutes if theywished. Exactly 180 minutes (3 hours) after administration of theplacebo or therapy subjects were tested via urinalysis for the presenceof ketones. If the subject tested positive the time to ketosis wasrecorded as 180 minutes (3 hours) and the test was complete. At the endof 180 minutes (3 hours) if a subject had not registered a positiveurine ketone test a second dose of the placebo or therapy wasadministered. Exercise was not completed after a second administrationof the placebo or therapy. Random urinalysis was completed when subjectscould micturate for the next six hours and the time to ketosis wasrecorded if subjects had a positive urine ketone test. At the end of thesix hour time period the test was complete for all subjects.

Tables 2-5 below detail the results of trial 2. Tables 2 and 3 belowdetail the data of the two randomized groups receiving placebos ortherapy and represent groups 1 and 2 respectively. Table 4 details thespecific data of subjects who completed trials 1 and 2. Table 5 detailsthe specific data of those who participated in trial 2 only.

TABLE 2 Investigation into the average time needed to reach ketosisthrough administration of the present invention, dietary carbohydraterestriction, and one round of exercise group 1. 1^(st) 2^(nd) Time toTotal dose Dose Ketosis Time Total Control Therapy Exercise 180 Therapyafter 2^(nd) Total to Time to Subject Urine Vs. Time Minute Vs. Dose InKetosis Ketosis Number Sex Test Placebo (Min) Urinalysis Placebo (Min)Ketosis (Min) (HR)  1 F − P 60 − P P 0 P P  2 M − P 57 − P P 0 P P  3† M− T 22 + 1 180 3  4 F − T 40 − T 345 1 345 5  5† F − T 80 − T 322 1 3225  6 M − T 55 + 1 180 3  7† F − T 20 − T 568 1 568 9  8 F − T 120 − T310 1 310 5  9 F − T 46 − P P 0 P P 10† M − T 60 + 1 180 3 11† M − P 46− T 331 1 331 5 12* F − T 120 * * * * * * 13 M − T 81 + 1 180 3 Average46% 58.3 4  5 9 288.62 4.55 Male 54% Female P = Placebo, T = Therapy.*Subject dropped out and data was not included final analysis.†Indicates subject also participated in trial one. Summary: Of thirteensubjects randomized to study group one, twelve subjects completed thefull study while one subject was discarded due to dropping out forpersonal reasons. Of the twelve subjects who completed the full studythree subjects did not enter ketosis while nine subjects did enterketosis. The three subjects who did not enter ketosis received placebos.Of the nine subjects who did enter ketosis four were found to be instate of ketosis after one dose and five subjects required two doses toenter ketosis. For those who did enter ketosis the average time spentexercising was 58.3 minutes (SD = 31.86) and the average time to ketosiswas found to be 288.44 minutes (SD = 128.35 min), 95% CI [189.8, 387.1]or 4.55 hours (SD = 1.94), 95% CI [3.06, 6.04].

TABLE 3 Investigation into the average time needed to reach ketosisthrough administration of the present invention, dietary carbohydraterestriction, and one round of exercise group 2. 1^(st) 2^(nd) Time toTotal dose Dose Ketosis Time Total Control Therapy Exercise 180 Therapyafter 2^(nd) Total to Time to Subject Urine Vs. Time Minute Vs. Dose InKetosis Ketosis Number Sex Test Placebo (Min) Urinalysis Placebo (Min)Ketosis (Min) (HR) 14† M (−) T 45 (−) T 318  1 318 5 15 F (−) P 56 (−) PP  0 P P 16 F (−) T 60 (+)  1 180 3 17† F (−) T 58 (+)  1 180 3 18 F (−)T 30 (−) T 240  1 240 4 19 F (−) T 60 (−) P P  0 P P 20 M (−) T 45 (+) 1 180 3 21† M (−) T 78 (+)  1 180 3 22* M* (+)* * * * * * * * * 23† M(−) P 35 (+)  1 180 3 24† F (−) T 30 (+)  1 180 3 25 M (−) T 56 (+)  1180 3 26 F (−) T 0 (−) T 315  1 315 5 Average 46% 43.7 7  3 10 213.3 3.5male 54% Female P = Placebo, T = Therapy. *Subject was excluded fromparticipating due to positive control urinalysis and data was notincluded in final analysis. †Indicates subject also participated intrial one. Summary: Of the thirteen subjects randomized to study grouptwo, twelve subjects completed the full study while one subject wasdisqualified due to a positive control ketone test. Of the twelvesubjects that completed the full study two subjects did not enterketosis while eight subjects did enter ketosis. The two subjects who didnot enter ketosis received placebos. Of the ten subjects that did enterketosis seven subjects were found to be in a state of ketosis after onedose and the remaining three subjects entered ketosis after two doseswere administered. For those who did enter ketosis the average timespent exercising was 43.7 minutes (SD = 21.50) and the average time toketosis was 213.3 minutes (SD = 57.52), 95% CI [172.2, 254.4] of 3.5hours (SD = 0.85), 95% CI [2.89, 4.11].

TABLE 4 Investigation into the average time needed to reach ketosis whenusing the present invention for subjects who also completed trial 1.1^(st) 2^(nd) Time to Total dose Dose Ketosis Time Total Control TherapyExercise 180 Therapy after 2^(nd) Total to Time to Subject Urine Vs.Time Minute Vs. Dose In Ketosis Ketosis Number Sex Test Placebo (Min)Urinalysis Placebo (Min) Ketosis (Min) (HR) 14† M (−) T 45 (−) T 318  1318 5  3† M (−) T 22 (+)  1 180 3  7† F (−) T 20 (−) T 568  1 568 9 17†F (−) T 58 (+)  1 180 3 10† M (−) T 60 (+)  1 180 3 11† M (−) P 46 (−) T331  1 331 5  5† F (−) T 81 (−) T 322  1 322 5 21† M (−) T 78 (+)  1 1803 23† M (−) P 35 (+)  1 180 3 24† F (−) T 30 (+)  1 180 3 Average 40%47.5 6  4 10 261.9 4.2 Male 60% Female P = Placebo, T = Therapy.†Indicates subject also participated in trial one. Summary: Analysis ofsubjects who completed trials 1 and 2. In both trials all ten subjectsreached a state of ketosis however the time needed to reach a state ofketosis was drastically reduced in trial 2 with the only differencebeing administration of the present invention. In trial 2 these subjectsexercised for an average of 47.5 minutes (SD = 21.59) and reached astate of ketosis in an average time of 261.9 minutes (SD = 127.12), 95%CI [171, 352.8] or 4.2 hours (SD = 1.93), 95% CI [2.82, 5.58].

TABLE 5 Investigation into the average time needed to reach ketosis whenusing the present invention for subjects who did not complete trial 1.1^(st) 2^(nd) Time to Total dose Dose Ketosis Time Total Control TherapyExercise 180 Therapy after 2^(nd) Total to Time to Subject Urine Vs.Time Minute Vs. Dose In Ketosis Ketosis Number Sex Test Placebo (Min)Urinalysis Placebo (Min) Ketosis (Min) (HR) 25 M (−) T 56 (+) 1 180 3 26F (−) T 0 (−) T 315 1 315 5 20 M (−) T 45 (+) 1 180 3 18 F (−) T 30 (−)T 240 1 240 4 16 F (−) T 60 (+) 1 180 3 13 M (−) T 81 (+) 1 180 3  8 F(−) T 120 (−) T 310 1 310 5  6 M (−) T 55 (+) 1 180 3  4 F (−) T 40 (−)T 345 1 345 5 Average 44.4% 54.1 5  4 9 234.4 3.77 Male 55.5% Female P =Placebo, T = Therapy. †Indicates subject also participated in study 1.Summary: Analysis of subjects who completed trial 2 only and were notinvolved in trial 1. Subjects completed exercise for an average time of54.1 minutes (SD = 33.3) and reached a state of ketosis in 234.4 minutes(SD = 70.1), 95% CI [180.5, 288.3] or 3.77 hours (SD = 0.92), 95% CI[3.063, 4.477]. Of note is that subject #26, an 85 year old female,received two doses of the present invention and entered ketosis in 5hours without completing any exercise.

Results.

Data analysis was conducted for the various studies with alpha criterionset at <0.05, the conventional level used to accept or reject data basedon statistical significance. A paired samples t-test of subjectscompleting trial 1 and trial 2 (data from tables 1 and 4) was conductedto evaluate the time required to enter ketosis after completing exerciseand restricting dietary carbohydrate vs. subjects completing exercise,restricting dietary carbohydrate, and receiving the present invention.There was a statistically significant difference revealed which was adecrease in mean time required for subjects to enter ketosis from trial1 (M=45.5, SD=13.85) to trial 2 (M=4.2, SD=1.93), t(9)=9.4635, p<0.0001(two-tailed) with the difference in the means from trial 1 to trial 2being 41.30 (hours) 95% CI [31.43,51.17].

A 41.30 hour reduction in the mean time required to enter ketosis fromtrial 1 to trial 2 represents a roughly 90% decrease in the total timerequired to reach ketosis when the present invention is used incombination with exercise and carbohydrate restriction as opposed todietary carbohydrate restriction and exercise alone.

A paired samples t-test of subjects completing trial 1 and 2 (data fromtables 1 and 4) was conducted to evaluate whether there was a differencein exercise routine time from trial 1 to trial 2 which may havecontributed to entering a state of ketosis faster. Analysis revealed nosignificant difference in the exercise routine from trial 1 (M=47,SD=21.10) to trial 2 (M=47.5, SD=21.59), t(9)=0.0432, p=0.9655(two-tailed) with difference in means of trial 1 and trial 2 being −0.50minutes 95% CI [−26.67, 25.67].

Data analysis results indicated that, through two trials, pairedsubjects were able to reduce the mean time required to enter ketosis byroughly 90% without increasing exercise time through utilizing thepresent invention in combination with dietary carbohydrate restrictionand exercise vs. dietary carbohydrate restriction and exercise alone.

An unpaired samples t-test of subjects completing trial 1 vs subjectscompleting trial 2 only (data from tables 1 and 5) was conductedutilizing Welch's method. The goal of the test was to evaluate the timerequired to enter ketosis for subjects completing exercise andrestricting dietary carbohydrate vs. subjects completing exercise,restricting dietary carbohydrate, and receiving the present invention.The subjects from trial 1 functioned as controls and were compared tosubjects who completed trial 2 only. There was a statisticallysignificant difference revealed which was a decrease in the mean timerequired for unpaired subjects to enter ketosis from trial 1 (M=45.5,SD=13.85) to trial 2 (M=3.77, SD=0.92), t(9)=9.686, p<0.0001(two-tailed) with a difference in the means of subjects from trail 1 totrial 2 being 41.72 hours, 95% CI [31.98,51.47]. A 41.72 hour reductionin the mean time required to enter ketosis represents roughly a 90%decrease in the total time required to reach ketosis when the presentinvention is used in combination with exercise and carbohydraterestriction as opposed to dietary carbohydrate restriction and exercisealone.

An unpaired samples t-test of subjects completing trial 1 vs subjectscompleting trial 2 only (data from tables 1 and 5) was conductedutilizing Welch's method. The goal of the test was to evaluate whetherthere was a difference in exercise routine time completed by subjectsfrom trial 1 vs subjects from trial 2. The subjects from trial 1functioned as controls and were compared to subjects who completed trial2 only. Analysis revealed no significant difference in exercise routinetime for unpaired subjects from trial 1 (M=47, SD=21.10) to trial 2(M=54.1 minutes, SD=33.3), t(13)=0.5482, p=0.5928 (two-tailed) with thedifference in means of trial 1 subjects and trial 2 subjects being 7.1minutes, 95% CI [−35.07,20.89]. Of note was that one subject an 85 yearold female entered ketosis in 315 minutes or 5.2 hours withadministration of two doses of the present invention without completingany exercise.

Data analysis results indicated that, through two trials, unpairedsubjects were able to reduce the mean time required to enter to ketosisby roughly 90% without increasing exercise time through utilizing thepresent invention in combination with dietary carbohydrate restrictionand exercise vs. dietary carbohydrate restriction and exercise alone.

Part of trial 2 was the evaluation of the efficacy of the presentinvention (therapy) to induce a state of ketosis vs. a placebo insubjects of two randomized groups who restricted carbohydrates andexercised. In group 1, the nine subjects who received the therapyentered ketosis while the three subjects receiving the placebo did not.One subject dropped out for personal reasons and was not included indata analysis. In group 2, the ten subjects who received the therapyentered ketosis while the two subjects receiving the placebo did not.One subject was found to have a positive urine ketone test prior tobeginning the trial and was excluded from participating. Of the 26 totalsubjects randomized to two groups all nineteen subjects who received thetherapy as part of the study entered ketosis, the five subjects whoreceived the placebo did not enter ketosis, one subject dropped out, andone subject was excluded.

An unpaired samples t-test of the two randomized, placebo controlledgroups was conducted utilizing Welch's method (data from tables 2 and3). The goal of the test was to evaluate whether there was a differencein the time required to enter ketosis between groups 1 and 2. The ninesubjects from group 1 who reached a state of ketosis were compared tothe ten subjects from group 2 who also reached a state of ketosis. Nosignificant statistical difference was seen in the mean time required toenter ketosis for group 1 (M=−4.2 hours SD=1.93) vs. group 2 (M=3.77,SD=0.92), t(10)=1.50, p=0.1633 (two-tailed) with the difference in themeans between group 1 and group 2 being 1.06, 95% CI [−0.51,2.62].

An unpaired samples t-test of the two randomized, placebo controlledgroups was conducted utilizing Welch's method (data from tables 2 and3). The goal of the test was to evaluate whether there was a differencein exercise routine time completed by subjects from group 1 vs. group 2.The nine subjects from group 1 who reached a state of ketosis werecompared to the ten subjects from group 2 who also reached a state ofketosis. No significant statistical difference was seen in the exerciseroutines in group 1 (M=58.3, SD=31.86) vs. group 2 (M=43.7, SD=21.50),t(15)=1.189, p=0.2560 (two-tailed) with the difference in the meansbetween group 1 and group 2 being 14.6, 95% CI [−11.75,40.95]

Data analysis results indicated that there was no significantstatistical difference in time required to reach ketosis or exerciseroutine time for individuals from group 1 vs. group 2 attempting toenter ketosis using the present invention in combination with dietarycarbohydrate restriction and exercise.

Taken in whole these results conclude that the present invention, whenused in combination with dietary carbohydrate restriction and exercise,drastically reduces the time required to enter a state of endogenousketone production.

Although the subject matter has been described in language specific tostructural features and/or methodological acts, it is to be understoodthat the subject matter defined in the appended claims is notnecessarily limited to the specific features or acts described above.Rather, the specific features and acts described above are disclosed asexample forms of implementing the claims.

I claim:
 1. A composition for rapidly inducing a state of endogenousketosis when the composition is accompanied with carbohydraterestriction in a maximum dosage of about 20 grams per day by a user, thecomposition comprising of: about 26.66-28.57 percent by mass of alphalipoic acid; about 0.01-0.02 percent by mass of chromium picolinate;about 47.61-49.99 percent by mass of L-arginine; about 23.33-23.81percent by mass of calcium carbonate; and, wherein the compositionfurther comprises zero percent by mass of ketones, zero percent by massof beta-hydroxybutyrate, and zero percent by mass of carbohydrate. 2.The composition of claim 1, wherein the composition is configured to beconsumed orally.
 3. A method for rapidly inducing a state of endogenousketosis when accompanied with carbohydrate restriction in a maximumdosage of about 20 grams per day by a user, the method comprising:restricting carbohydrate consumption to the maximum dosage of about 20grams per day; and, consuming a composition comprising: zero percent bymass of ketones, zero percent by mass carbohydrates, and zero percent bymass beta-hydroxybutyrate; about 26.66-28.57 percent by mass of alphalipoic acid; about 0.01-0.02 percent by mass of chromium picolinate;about 47.61-49.99 percent by mass of L-arginine; and, about 23.33-23.81percent by mass of calcium carbonate.
 4. The method of claim 3, whereinsaid carbohydrate restriction of the maximum dosage of about 20 grams isprior to consumption of the composition.
 5. The method of claim 3,wherein the consumption of the composition is on an empty stomach. 6.The method of claim 5, wherein about thirty minutes after consumption ofthe composition the user performs moderate intensity exercise.
 7. Themethod of claim 5, wherein about three hours after consuming a firstdose of the composition, the user tests for a presence of ketones inurine utilizing at least one sodium nitroprusside urine ketone reagentstrip.
 8. The method of claim 7, wherein if a state of endogenousketosis has not been reached as indicated by a positive ketone testutilizing the at least one sodium nitroprusside urine ketone test stripthen a user consumes a subsequent dose of the composition.
 9. The methodof claim 8, wherein beginning about one hour after consuming thesubsequent dose of the composition, the user randomly tests for thepresence ketones in urine utilizing the at least one sodiumnitroprusside urine ketone reagent strip until a state of endogenousketosis has been reached.
 10. The composition of claim 1, wherein a sumtotal weight of the alpha lipoic acid, the chromium picolinate, theL-arginine, and the calcium carbonate is from 2100.2 to 3000.5 mg.
 11. Acomposition for rapidly inducing a state of endogenous ketosis when thecomposition is accompanied with carbohydrate restriction in a maximumdosage of about 20 grams per day by a user, the composition comprising:600 to 800 mg of alpha lipoic acid; 200 to 500 micrograms of chromiumpicolinate; 1000 to 1500 mg of L-arginine; 500 to 700 mg of calciumcarbonate; and, wherein the composition further comprises zero grams ofketones, zero grams of beta-hydroxybutyrate, and zero grams ofcarbohydrates.
 12. The composition of claim 11, wherein the compositionis configured to be consumed orally.